Introduction

The term adaptogen was introduced into scientific literature by Russian toxicologist Nikolay Lazarev in 1957 to refer to substances that increase the “state of non-specific resistance” in stress.^1,2 His concept was based on Hans Selye’s theory of stress and general adaptation syndrome,³ which has 3 phases: alarm phase, phase of resistance, and phase of exhaustion (Figure 1).*

Later, another Soviet scientist, pharmacologist Israel Brekhman, postulated that adaptogens must be safe and normalize body functions irrespective of the nature of stressors.^6,7

Other definitions of adaptogens are also associated with physiological conditions:

• Adaptogenic substances are stated to have the capacity to normalize body functions and strengthen systems compromised by stress. They are reported to have a protective effect on health against a wide variety of environmental assaults and emotional conditions.⁸
• Adaptogens are innocuous agents, nonspecifically increasing resistance against physically, chemically, biologically, and psychologically noxious factors (“stressors”), normalizing effect independent of the nature of pathologic state.^6,7
• Adaptogens are substances that elicit in an organism a state of nonspecifically raised resistance, allowing them to counteract stressor signals and to adapt to exceptional strain.⁹

As a pharmacotherapeutic group, adaptogens were recently defined as herbal preparations that increased attention and endurance in fatigue, and reduced stress-induced impairments and disorders related to the neuro-endocrine and immune systems.^5,10 This definition was based on evidence obtained from clinical trials, which authors evaluated in accordance with the European Medicines Agency Assessment Scale and the Jadad scale—a recognized, evidence-based, validated grading rationale for clinical trials. Today, the term adaptogen is widely used by many herbalists although it has yet to gain prominence in mainstream pharmacology.

In this context, the pharmacological profile of various adaptogenic plants might be different from plant to plant, but what is common for true adaptogens is their ability to increase the state of non-specific resistance and to be safe in long-term use in the appropriate dose level.^4,5,9-16 The term adaptogen is often applied to plants (Table 1) even when the criteria of an adaptogen have not been met, such as the important and significant general adaptive effect on stress involving the whole organism and its main functions.¹⁶ Indeed, systematic pharmacological assessment of traditionally used tonics (possible adaptogens) show that some of them do not meet criteria common for adaptogens by definition.¹⁷

It is not easy to find true scientific information about adaptogens on the Internet, since original scientific data and articles are significantly diluted by the plethora of pseudo-scientific compilations,^18-28 deliberately used by opponents of adaptogens in order to criticize and discredit the entire adaptogenic concept and the large body of research that has been conducted during the last 50 years.

In this review, the authors have attempted to summarize the research on adaptogens from the very beginning to the present time, with particular concentration on their evidence-based pharmacological and clinical effects and the molecular mechanisms of action.

History of Research on Adaptogens

The history of modern scientific research on adaptogens begins with World War II, with the enhanced need to increase stamina, endurance, and performance of soldiers, pilots, sailors, and civilians engaged in production of weapons and war material.

For example, the first scientific studies on the stimulating and tonic effects of schisandra (Schisandra chinensis, Schisandraceae) were published in Soviet World War II-era military journals (Figure 2).¹³

Apparently, the Russian interest in S. chinensis (known as limonnik in Russian) arises from ethnopharmacological investigations by V.L. Komarov (1895) and V. Arsenyev (1903-1907) in far-eastern Siberia and northern Manchuria. The berries and seeds were determined to have been used by Nanai hunters (a native people of far-eastern Siberia and Chinese Manchuria, who are also known as Goldis or Samagir) as a tonic; to reduce thirst, hunger and exhaustion; and to improve night-time vision.¹³

In the early 1960s, the study of adaptogens developed into a field of biomedicinal research in its own right in the former USSR. The extent of the research carried out was enormous, with over 1,000 studies published in the USSR until 1982. Most of these studies concerned extracts or isolates prepared from eleuthero (Eleutherococcus senticosus, Araliaceae; formerly referred to as “Siberian ginseng” in the United States) root, schisandra berry, Asian ginseng (Panax ginseng, Araliaceae) root, and golden root (Rhodiola rosea, Crassulaceae) root.^{6, 7, 12-14, 29, 30}

Extensive research revealed that adaptogens possessed stimulatory effects, and on this basis, adaptogens achieved recognition in the official medicine of Russia in the early 1960s. Adaptogens were determined to be useful in the Soviet space exploration program as well as Arctic and Antarctic expeditions, Olympic games, chess competitions, in the nuclear energy industry, and many other stressful situations and conditions in the former USSR.

However, all these studies were published in Russian-language journals; thus, they are relatively difficult to access. Several review articles on adaptogens published in English in the 1980s and 1990s by Brekhman and Dardimov (19686); Farnsworth et al. (1985²⁹); Wagner et al. (1994⁹, 1995¹¹); Panossian et al. (1999^4,31); and Davydov and Krikorian (200032) increased to some extent professional attention to adaptogens. This professional interest particularly occurred in Indian and Chinese scientists who were researching medicinal plants such as the traditional Ayurvedic tonic ashwagandha (Withania somnifera, Solanaceae) and the revered Asian (also known as Chinese) ginseng (P. ginseng). Each plant is used in its respective traditional medicinal system as a tonic and nourishing agent for fatigue and deficiency of prana (the life vital energy, activating body and mind in Ayurveda) and qi (vital energy in Traditional Chinese Medicine [TCM]) and jing (essence or the state of health and lifespan in TCM), respectively. Figure 3 reflects the significant growth and interest in adaptogen research since 1940, the growth in the past few decades—due in part to the impact of the Swedish Herbal Institute and its contribution of controlled clinical trials of adaptogens^33-40—and studies on elucidation of molecular mechanisms of their action.^15,41-46

Some of the most interesting developments are pharmacological studies that clearly indicate that certain adaptogenic substances can activate the protective mechanisms of cells, which is linked to an increase in survival rate both in vitro and in vivo.^41-47 These studies have so far been directed at the regulation of molecular chaperones (Heat Shock Proteins), such as Hsp70^45,46 and other key stress mediators.¹⁵

Possible Indications for Use for Adaptogens and the Level of Scientific Evidence

The normal therapeutic medical paradigm—one drug for one disease—is not appropriate for adaptogens as they can have numerous pharmacological effects and indications. Tables 2 and 3 show their pharmacological profiles, which are different, but similar in terms of their stress-protective action. Therefore, all of these pharmacological effects can be combined into the groups associated with stimulating and stress-protective effects in the central nervous system (CNS) and vegetative nervous systems, the endocrine system, and the immune system, comprising by definition the parts of a neuroendocrine-immune complex-stress-system.

Apparently, stimulating (acute/single dose effect) and tonic (effect of repeated/multiple administration) effects of adaptogens are actually consequences of their stress-protective activity.

The CNS-stimulating and tonic effects of adaptogens are well documented in numerous publications and reviews.¹⁴ In contrast to conventional stimulants, such as sympathomimetics (e.g., ephedrine, fenfluramine, phentermine, prolintane) and general tonics, the adaptogens do not possess addiction, tolerance, and abuse potentials; they do not impair mental function; and they do not lead to psychotic symptoms in long-term use (see Table 4). Their clinical and pharmacological effects are due to a different mode of action. Their stimulating effect is more pronounced against a background of fatigue and stress.

The most important characteristics of adaptogens, such as stress-protection and a stimulatory effect, are common to all adaptogens. However, the effects may differ under various circumstances (Tables 2 and 3) as has been documented in a number of clinical studies (Table 5) and reviews. One such review²⁹ focused on over 35 clinical trials on E. senticosus in healthy human subjects (ca. 6,000 subjects, ages 19 to 72), which were performed in normal and stressful conditions (e.g., high-temperature environment, forced work periods, loud noise conditions, motion sickness, varying degrees of deafness, heavy physical burden, hypertension, mountain rescuers under forced conditions, athletes, deep-sea divers, intense mental work and physical work, and factory workers under extreme working conditions). There was an improvement of the physical and mental work capacities in all cases. In addition, over 35 studies have focused on the effect of E. senticosus on more than 2,200 patients with a pathology. The studies included patients with atherosclerosis, acute pyelonephritis, diabetes, hypertension, trauma, neuroses, rheumatic heart disease, chronic bronchitis, insomnia, cancer, and several other ailments. In most cases, a moderate improvement relative to the initial conditions was observed.⁷ The extracts were well-tolerated and no adverse effects were observed.

However, the most convincing evidence of the efficacy of adaptogens were found in studies related to their neuro-protective effects, effects on cognitive functions and mental performance in fatigue,¹⁰ and on their efficacy in asthenia and depression.^{5,10, 33-40} The evidence suggests that adaptogens may be beneficial on neurodegenerative disorders.

Adaptogens in Fatigue, Effect on Cognitive Functions

In total, more than 30 publications on the clinical efficacy of various R. rosea preparations can be found in the US National Library of Medicine’s PubMed database. The majority of these studies are of varying methodological rigor and concern cognitive functions and mental performance under fatigue (Table 5).

The clinical trials using S. chinensis (13 studies) and E. senticosus (11 studies) on mental performance in humans have been the subject of a recent review.¹⁰ A systematic review showed that adaptogens have a significant, beneficial, and specific effect on stress-induced symptoms under fatigue.¹⁰ It was observed that R. rosea, in particular, significantly reduced symptoms of fatigue and improved attention after 4 weeks of repeated administration.³⁹ Moreover, studies on healthy volunteers receiving single and repeated doses of the proprietary SHR-5^® extract (R. rosea root; Swedish Herbal Institute; Gothenberg, Sweden) have demonstrated an anti-fatigue effect and improvement in cognitive functions during fatigue and in stressful conditions.^33,34 Thus, one may conclude that repeated administration of R. rosea extract (SHR-5) exerts an anti-fatigue effect on healthy subjects and burnout patients expressing fatigue syndrome. This in turn increases the patient’s mental performance and ability to concentrate.

Adaptogens in Asthenia and Psychiatric Disorders⁵

In general, the clinical studies carried out in the USSR are the most questionable and poorly documented, as standardized psychological measures were not used in the earlier studies. Indeed, some of them did not use randomization or blinding of subjects. However, the main problem in assessment of these studies is that the Soviet diagnostic criteria were different from commonly used criteria in the rest of the world. The diagnostic criteria used in the USSR prior to 1990 for schizophrenia was particularly idiosyncratic, overused, and misapplied to other conditions. The diagnoses of asthenia and neuroasthenia include a very heterogeneous group of patients with mixed psychological and physical disorders, making the studies more difficult to interpret. Nevertheless, despite numerous shortcomings that reduced the quality of evidence obtained in the early clinical studies in the USSR, this scientific evidence provides important information about the efficacy and safety of adaptogens in the treatment of psychiatric disorders (Table 5). For example, encouraging results from a randomized, double-blind, placebo-controlled study exist for use of SHR-5 rhodiola extract in mild-to-moderate depression.³⁸

Active Principles and Molecular Mechanisms of Action of Selected Adaptogens

The phenolic compounds include phenylpropanoids and phenylethane derivatives such as salidroside (rhodioloside), rosavin, syringin, triandrin, tyrosol, and lignans such as eleutheroside E and schisandrin B. They are structurally similar to the catecholamines—the mediators of the sympathoadrenal system (SAS) involved in activation of the stress system in the early stages of stress response. The tetracyclic triterpenoids, such as cucurbitacin R diglucoside, ginsenosides, and phytosterol-glycosides (e.g., eleutheroside A, sitoindosides, daucosterol) structurally resemble the corticosteroids that act as stress hormones involved in protective inactivation of the stress system. Salidroside—the primary active principle of rhodiola extracts—was found to have neuroprotective activity, which reduced stress-induced impairments and disorders related to the neuro-endocrine and immune systems. A number of these findings might raise the possibility of potential therapeutic applications of salidroside in preventing and treating cerebral ischemic and neurodegenerative diseases. Tyrosol— another active principle of rhodiola extract—increases phosphorylation of nitric oxide synthase eNOS and Forkhead box O (FOXO) transcription factor FOXO3a, which are key molecular targets involved in this mechanism. Furthermore, tyrosol has recently been shown to induce the expression of the longevity protein SIRT1.⁴⁹

Administration of the amino acid tyrosine, which is a common precursor of biosynthesis of tyrosol, salidroside, and catecholamines (Figure 4), alleviates both stress-induced depletion of brain catecholamines (norepinephrine and dopamine in the alarm phase of stress syndrome) and reduces fatigue, as noted in animal task performances.⁵⁰ A number of clinical studies suggest that supplementation of tyrosine might improve stress-induced (e.g., cold, noise, anxiety, and fatigue) accuracy of mental performance.⁵¹

Indeed, schisandrin B has a similar pharmacological profile associated with stress-protective activity. Apparently, the neuroprotective effect of schisandrin B^52,53 is associated with the expression of heat shock proteins Hsp70.^54-58 Schisandrin B stimulates the expression of Hsp70 in normal cells, which is associated with the enhancement of mitochondrial glutathione status, antioxidant activity, adenosine triphosphate (ATP) generation, mitigation of age-related impairments in mitochondrial antioxidant status and functional ability in various tissues, enhancement in cognitive functions, and an increase in the survival of aging in rodents.^58,59

The stress-protective effect of adaptogens has been demonstrated on simple organisms and on isolated cells.^41,43,47 Thus, there may be an association with regulation and homeostasis of the neuro-endocrine-immune complex. In addition, there may also be a connection with more evolutionary, conservative mechanisms of regulation in cellular homeostasis and the adaptive/defense response to external stressors. Such a defense system is apparently common for all cells and living organisms and probably includes heat shock proteins among the number of key mediators of innate nonspecific resistance to stressors.

The same mechanism can be found in stress tolerance and lifespan extension, which makes them parallel phenomena. Therefore, it is not surprising that adaptogens prolong the lifespan of the nematode Caenorhabditis elegans⁴² and Drosophila melanogaster⁵⁹ in a dosedependent manner.

The beneficial stress-protective activity of adaptogens was associated with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of the stress response common to all cells, such as the following:

• Heat shock proteins Hsp70 and Hsp16, which are molecular chaperones involved in stress-induced cytoprotection and in adaptation of repeated exposure to an initial stressor;^43,45,46
• Stress-activated c-Jun N-terminal protein kinase 1 (JNK1);¹⁵
• FOXO transcription factor DAF-16;⁴²
• HPA-axis, including cortisol and glucocorticoid receptors (GRs);¹⁵
• Beta-endorphine;⁵
• NO15
• The biosynthesis of ATP, thus inducing an alteration in energy source.⁵

A hypothetical molecular mechanism of action of adaptogens is outlined in Figure 5.^5,10

Typically, a cell is in one of the following states:

• balance (dynamic equilibrium—homeostasis);
• functioning under stressful conditions (threatened homeostasis—imbalance);
• the state of adaptation (tolerance) to stress (i.e., state of nonspecific resistance to stress;
• heterostasishomeostasis with a higher level of equilibrium); or
• the state of apoptosis (normally programmed cell death).

The upper panel in Figure 5 shows that mitochondria generate aggressive oxygen-containing radicals that can damage native or repair proteins by distorting their 3-D structure, so that they can no longer fulfill their functions in the cell.

There are many “players” involved in the regulation of homeostasis at both the cellular level and the organism level, such as:

• the stress hormone cortisol (a molecule that is secreted from glands and regulates the functions of organs and systems of the organism);
• GRs that modulate/regulate cortisol secretion (feedback regulation);
• NO, an intracellular signaling molecule that mediates stress response and modulates stress-induced activation of hormonal, nervous, and immune systems;
• FOXO, a Forkhead protein that controls the synthesis of proteins involved in stress resistance, cell survival, and longevity. When it is in the cytoplasm of the cell, DNA produces proteins involved in growth and development of cells, when FOXO is translocated into the nucleus and binds to DNA. The cell starts to produce other proteins that are involved in resistance to stress and increases survival and longevity.

Under stress (e.g., infection, cold, heat, radiation, physical load, emotional stress), an external stress signal activates a cascade of “signalling” proteins/enzymes including JNK, a stress-activated enzyme that plays important roles in the regulation of a diverse array of cellular functions such as neuronal development, activation of the immune system, and programmed cell death (apoptosis). The functions of JNK are as follows:

• To increase the formation of aggressive radicals and NO, which in turn suppresses the generation of energy-providing molecules, e.g., ATP. As a result of lack of energy, many proteins cannot function properly, several functions are suppressed, and the first symptoms of fatigue and exhaustion are observed. ATP is also required for the normal functioning of heat shock proteins (e.g., Hsp70), which are produced as a defense response to stress and assist in the repair of misfolded and damaged proteins.
• To regulate a diverse array of cellular functions, including neuronal development, activation of immune system, and programmed cell death (apoptosis).
• To suppress GRs such that the feedback inhibition of cortisol secretion ceases to function and levels of circulatory cortisol increase. The cortisol inhibits the immune system, and has anti-inflammatory effects on the body. It is also required to protect the organism from over-reaction/over-activation in response to stress. However, chronically high levels of cortisol are associated with depression, chronic fatigue, and impaired cognitive function, such as decreased attention and learning ability.
• To activate translocation of FOXO to the nucleus and initiates the synthesis of proteins that confer stress-resistance and increased longevity. The lower panel in Figure 5 shows that adaptogen preparations, such as ADAPT-232, decrease inducible NO, cortisol, and JNK under stress and stimulate/activate the expression of Hsp70 and p-FOXO1.

The stimulation of Hsp70 biosynthesis is a key point in the mechanism of action of adaptogens since the heat shock protein is responsible for the following actions:

• enhances the repair of damaged proteins;
• inhibits the stress-induced expression of NO genes and, since the reduced levels of inducible NO cannot suppress the formation of energy providing molecules, ATP is increased to normal levels in the adapted cell;
• inhibits JNK and consequently apoptotic deaths and suppression of immune system via activation of GRs and other mechanisms. Normal GR function and normal ATP levels are associated with the anti-fatigue and anti-depressive effects of adaptogens and with normal cognitive function (good attention, memory, and learning);
• is probably associated with the effect of adaptogens on the phosphorylation of FOXO and its translocation into the nucleus of isolated cells (i.e., human monocytes) or simple organisms (i.e., DAF-16 in C. elegans and, consequently, with increased resistance to stress and increased lifespan).

In summary, ADAPT-232 works like a stress vaccine (stress-mimetic) by activating stress-induced self-defense mechanisms in order to adapt the cell and organism to mitigate stress-induced harmful effects.

It seems that activation of Hsp70 expression is a key point in the mode of action of adaptogens. Studies demonstrate that adaptogens induce an increase of serum Hsp72 in animals. This induction is considered a defense response to stress, which increases tolerance to stress in a combination of physical and emotional stresses. This data suggest that increased tolerance to adaptogen-induced stress is associated with its stimulation of expression of circulating serum Hsp72.^45,46 In fact, Hsp72 expression and release is a known mediator of the stress response involved in repairing proteins during physical load. The working hypothesis of this research is that adaptogens adapt (or make less sensitive) the organism to stress. Thus, adaptogens act like low molecular weight “vaccines” or stress-mimetics, which induce mild activation of the stress system in order to cope with more severe stress. The adaptogens act as challengers and mild stressors (stress-mimetics). This gives rise to adaptive and stress-protective effects, which are mainly associated with the hypothalamicpituitary-adrenal (HPA) axis, a part of the stress system that also contributes to the nervous, cardiovascular, immune, gastrointestinal, and endocrine systems.

The antidepressive effect of R. rosea^38,44 may be associated with parts of the stress system (e.g., secretion of cortisol and the JNKmediated effects on the glucocorticoid receptors).¹⁵

Conclusions and Perspectives

Recent pharmacological studies of some adaptogens give a rationale to their effects at the molecular level. Research demonstrates that the beneficial stress-protective effect of adaptogens is related to the regulation of homeostasis via several mechanisms of action, which are associated with the HPA axis and the regulation of key mediators of the stress response, such as molecular chaperones (e.g., Hsp70), stress-activated JNK1, FOXO transcription factor, cortisol, and NO.^5,10

In summary, adaptogens may be regarded as a novel pharmacological category of anti-fatigue agents that perform the following functions:

• induce increased attention and endurance in situations of decreased performance caused by fatigue and/or sensation of weakness;
• reduce stress-induced impairments and disorders related to the function of stress (neuro-endocrine and immune) systems.

Adaptogens have not only specific therapeutic effects in some stress-induced and stress-related disorders, but may also have an impact on the quality of life of patients when implemented as adjuvants in the standard therapy of many chronic diseases and pathological conditions (e.g., post-surgery recovery, asthenia, congestive heart failure, chronic obstructive pulmonary disease). Adaptogens may also have potential use in age-related disorders, such as neurodegenerative diseases and cardiovascular diseases. Thus, elderly people may be able to maintain their health status on a normal level, improve their quality of life, and possibly increase longevity. However, further research is needed to evaluate the efficacy of adaptogens as geriatric agents and to elucidate molecular mechanisms of action of these complex herbal extracts and their active principles.

Alexander Panossian, PhD, Dr.Sci., is Research Projects Director at the Swedish Herbal Institute, a forprofit company which produces proprietary phytomedicines, most of which are adaptogenic. He obtained his scientific degrees in Moscow Institute of Bioorganic chemistry in 1975, and in Moscow Institute of Fine Chemical Technology in 1986. After the collapse of the USSR in 1991, Dr. Panossian was made a full professor of chemistry of natural and physiologically active compounds in the Russian Federation and later served as Director of Laboratory of Quality Control of Drugs of the Medical Drug Agency of the Republic of Armenia. In 2003, he moved to Sweden where he is currently working at the Swedish Herbal Institute. During his scientific career he was temporarily working as a guest scientist in the laboratory of Nobel Laureate B. Samuelsson at the Karolinska Institute (1982-83), at Munich University (1993-5), and at King’s College in London, 1996. He has written or co-authored more than 170 articles in peer-reviewed journals.

Hildebert Wagner, PhD, is Professor Emeritus at the Institute for Pharmaceutical Biology at the University of Munich in Germany. He is the author of 7 books including: Plant Drug Analysis (Springer Verlag Heidelberg, 1996), and Drugs and Drug Constituents (Wissenschaftliche Verlagsgesellschaft Stuttgart, 1998), as well as authoring over 900 scientific publications. Dr. Wagner was made a full professor of pharmacognosy in 1965, and later served as director of the Institute of Pharmaceutical Biology in Munich until 1999. He has been distinguished by many international scientific institutions, including the Universities of Ohio, Budapest and Debrecen, Dijon, and Helsinki for his work in pharmacognosy. Dr. Wagner sits on advisory/editorial boards for Phytochemistry, the Journal of Ethnopharmacology, the Journal of Natural Products, as well as serving as Founding Editor for the international journal Phytomedicine. He is the recipient of the American Botanical Council’s Norman R. Farnsworth Excellence in Botanical Research Award in 2008.

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*For this review, the authors used original full-text Russian articles published from 1943. The word adaptogen is not found in any publication before 1958, even in N.V. Lazarev’s comprehensive book Evolution of Pharmacology (1947) or any of his or I.I. Brekhman’s publications (or conference abstracts) pre-1958. The first study on nonspecific resistance (adaptogenic) activity of a synthetic drug Dibazol was published in 1956 (and a conference abstract in 1947), but with no mention of “adaptogen” or “adaptogenic activity.” Earlier studies on schisandra were initiated and published in 1943-47; they discussed its stimulating activity.